Journal of Viral Hepatitis

Volume 14, Issue 11 p. 767-774

Differences of YMDD mutational patterns, precore/core promoter mutations, serum HBV DNA levels in lamivudine-resistant hepatitis B genotypes B and C

X. P. Pan,

X. P. Pan

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

L. J. Li,

L. J. Li

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

W. B. Du,

W. B. Du

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

M. W. Li,

M. W. Li

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

H. C. Cao,

H. C. Cao

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

J. F. Sheng,

J. F. Sheng

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

X. P. Pan,

X. P. Pan

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

L. J. Li,

L. J. Li

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

W. B. Du,

W. B. Du

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

M. W. Li,

M. W. Li

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

H. C. Cao,

H. C. Cao

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

J. F. Sheng,

J. F. Sheng

Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Search for more papers by this author

First published: 27 April 2007

https://doi.org/10.1111/j.1365-2893.2007.00869.x

Citations: 18

Lan Juan Li, Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China. E-mail: [email protected], [email protected]

Read the full text

About

PDF

Tools

Share a link

Email
Facebook
Twitter
LinkedIn
Reddit
Wechat

Abstract

Summary. The aims of this study were to investigate the viral differences among lamivudine-resistant hepatitis B virus (HBV) genotypes B and C in vivo. Fifty-three patients carrying lamivudine-resistant HBV were enrolled in this study. HBV genotypes, Levels of alanine aminotransferase (ALT), HBV DNA levels were monitored during therapy. The polymerase and precore/core promoter genes were amplified by polymerase chain reaction and their products were sequenced directly. Among 53 patients resistant HBV genotypes B and C accounted for 41.50% and 58.50%, respectively. The occurrence of reverse transcriptase rt204I mutants was lower in genotype B (36.36%) than that in genotype C (87.10%), whereas rt204V mutants was higher in genotype B (63.64%) than that in genotype C (12.90%). The occurrence of precore mutation (nt1896A) was higher in genotype B (77.27%) than that in genotype C (32.26%). Serum HBV DNA levels after emergence of lamivudine resistance were higher in genotype C (7.71 ± 0.80 Log copies/mL) compared with genotype B (6.97 ± 0.77 Log copies/mL). Multivariate analysis identified pretreatment HBV DNA levels, HBeAg status and HBV genotype as independent factors associated with a shorter time to lamivudine resistance(P = 0.035, P = 0.006 and P = 0.001, respectively). Multivariate analysis showed that HBV genotype (P = 0.004) and pretreatment ALT levels (P = 0.01) was independently associated with YMDD mutational patterns. The results showed that the YMDD mutational patterns, precore mutation and serum HBV DNA levels differ between lamivudine-resistant HBV genotypes B and C in vivo. It is valuable for treatment of lamivudine-resistant HBV in clinic.

References

1 Lee WM. Hepatitis B virus infection. N Engl J Med 1997; 337: 1733–1745.
10.1056/NEJM199712113372406
CASPubMedWeb of Science®Google Scholar
2 Chen DS. From hepatitis to hepatoma: lessons from type B viral hepatitis. Science 1993; 262: 369–370.
10.1126/science.8211155
CASPubMedWeb of Science®Google Scholar
3 Dienstag JL, Schiff ER, Wright TL et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999; 341: 1256–1263.
10.1056/NEJM199910213411702
CASPubMedWeb of Science®Google Scholar
4 Lai CL, Chien RN, Leung NW et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998; 339: 61–68.
10.1056/NEJM199807093390201
CASPubMedWeb of Science®Google Scholar
5 Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med 1995; 333: 1657–1661.
10.1056/NEJM199512213332501
CASPubMedWeb of Science®Google Scholar
6 Dienstag JL, Goldin RD, Heathcote EJ et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003; 124: 105–117.
10.1053/gast.2003.50013
CASPubMedWeb of Science®Google Scholar
7 Tipples GA, Ma MM, Fischer KP, Bain VG, Kneteman NM, Tyrrell DL. Mutation in HBV RNA-dependent DNA polymerase confers resistance to lamivudine in vivo. Hepatology 1996; 24: 714–717.
10.1002/hep.510240340
CASPubMedWeb of Science®Google Scholar
8 Allen MI, Deslauriers M, Andrews CW et al. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology 1998; 27: 1670–1677.
10.1002/hep.510270628
CASPubMedWeb of Science®Google Scholar
9 Ono-Nita SK, Kato N, Shiratori Y et al. YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance: a study by in vitro full-length viral DNA transfection. Hepatology 1999; 29: 939–945.
10.1002/hep.510290340
CASPubMedWeb of Science®Google Scholar
10 Ling R, Mutimer D, Ahmed M et al. Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine. Hepatology 1996; 24: 711–713.
10.1002/hep.510240339
CASPubMedWeb of Science®Google Scholar
11 Yuen MF, Sablon E, Hui CK, Yuan HJ, Decraemer H, Lai CL. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology 2001; 34: 785–791.
10.1053/jhep.2001.27563
CASPubMedWeb of Science®Google Scholar
12 Bartholomew MM, Jansen RW, Jeffers LJ et al. Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet 1997; 349: 20–22.
10.1016/S0140-6736(96)02266-0
PubMedWeb of Science®Google Scholar
13 Leung NW, Lai CL, Chang TT et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 2001; 33: 1527–1532.
10.1053/jhep.2001.25084
CASPubMedWeb of Science®Google Scholar
14 Liaw YF, Chien RN, Yeh CT, Tsai SL, Chu CM. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy. Hepatology 1999; 30: 567–572.
10.1002/hep.510300221
CASPubMedWeb of Science®Google Scholar
15 Wang JH, Lu SN, Lee CM, Lee JF, Chou YP. Fatal hepatic failure after emergence of the hepatitis B virus mutant during lamivudine therapy in a patient with liver cirrhosis. Scand J Gastroenterol 2002; 37: 366–369.
10.1080/003655202317284309
CASPubMedWeb of Science®Google Scholar
16 Kao JH, Wu NH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes and the response to interferon therapy. J Hepatol 2000; 33: 998–1002.
10.1016/S0168-8278(00)80135-X
CASPubMedWeb of Science®Google Scholar
17 Wai CT, Chu CJ, Hussain M, Lok AS. HBV genotype B is associated with better response to interferon therapy in HBeAg (+) chronic hepatitis than genotype C. Hepatology 2002; 36: 1425–1430.
10.1002/hep.1840360619
CASPubMedWeb of Science®Google Scholar
18 Kao JH, Liu CJ, Chen DS. Hepatitis B viral genotypes and lamivudine resistance. J Hepatol 2002; 36: 303–304.
10.1016/S0168-8278(01)00246-X
PubMedWeb of Science®Google Scholar
19 Ben-Ari Z, Daudi N, Klein A et al. Genotypic and phenotypic resistance: longitudinal and sequential analysis of hepatitis B virus polymerase mutations in patients with lamivudine resistance after liver transplantation. Am J Gastroenterol 2003; 98: 151–159.
10.1111/j.1572-0241.2003.07178.x
CASPubMedWeb of Science®Google Scholar
20 Chien RN, Yeh CT, Tsai SL, Chu CM, Liaw YF. Determinants for sustained HBeAg response to lamivudine therapy. Hepatology 2003; 38: 1267–1273.
10.1053/jhep.2003.50458
CASPubMedWeb of Science®Google Scholar
21 Zollner B, Petersen J, Puchhammer-Stockl E et al. Viral features of lamivudine resistant hepatitis B genotypes A and D. Hepatology 2004; 39: 42–50.
10.1002/hep.20016
CASPubMedWeb of Science®Google Scholar
22 Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2001; 34: 1225–1241.
10.1053/jhep.2001.29401
CASPubMedWeb of Science®Google Scholar
23 Usuda S, Okamoto H, Iwanari H et al. Serological detection of hepatitis B virus genotypes by ELISA with monoclonal antibodies to type-specific epitopes in the preS2-region product. J Virol Methods 1999; 80: 97–112.
10.1016/S0166-0934(99)00039-7
CASPubMedWeb of Science®Google Scholar
24 Sun J, Wang Z, Ma S et al. Clinical and virological characteristics of lamivudine resistance in chronic hepatitis B patients: a single center experience. J Med Virol 2005; 75: 391–398.
10.1002/jmv.20281
CASPubMedWeb of Science®Google Scholar
25 Abe A, Inoue K, Tanaka T et al. Quantitation of hepatitis B virus genomic DNA by real-time detection PCR. J Clin Microbiol 1999; 37: 2899–2903.
10.1128/JCM.37.9.2899-2903.1999
CASPubMedWeb of Science®Google Scholar
26 He ML, Wu J, Chen Y, Lin MC, Lau GK, Kung HF. A new and sensitive method for the quantification of HBV cccDNA by real-time PCR. Biochem Biophys Res Commun 2002; 295: 1102–1107.
10.1016/S0006-291X(02)00813-6
CASPubMedWeb of Science®Google Scholar
27 Jun-Bin S, Zhi C, Wei-Qin N, Jun F. A quantitative method to detect HBV cccDNA by chimeric primer and real-time polymerase chain reaction. J Virol Methods 2003; 112: 45–52.
10.1016/S0166-0934(03)00190-3
CASPubMedWeb of Science®Google Scholar
28 Lai CL, Chien RN, Leung NW et al. A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med 1998; 339: 61–68.
10.1056/NEJM199807093390201
CASPubMedWeb of Science®Google Scholar
29 Liaw YF, Leung NW, Chang TT et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology 2000; 119: 172–180.
10.1053/gast.2000.8559
CASPubMedWeb of Science®Google Scholar
30 Leung NW, Lai CL, Chang TT et al. Extended lamivudine treatment in patients with chronic hepatitis B enchances hepatitis B e antigen seroconversion rates: results after three years of therapy. Hepatology 2001; 33: 1527–1532.
10.1053/jhep.2001.25084
CASPubMedWeb of Science®Google Scholar
31 Tian Y, Du SC, Zhang R, Wei L, Chen Y, Han JD. YVDD is the primary symbol of gene mutation in hepatitis B patients treated with lamivudine. Zhonghua Gan Zang Bing Za Zhi 2005; 13: 455–456.

CASPubMedGoogle Scholar
32 Akuta N, Suzuki F, Kobayashi M et al. The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment. J Hepatol 2003; 38: 315–321.
10.1016/S0168-8278(02)00410-5
CASPubMedWeb of Science®Google Scholar
33 Suzuki F, Tsubota A, Arase Y et al. Efficacy of lamivudine therapy and factors associated with emergence of resistance in chronic hepatitis B virus infection in Japan. Intervirology 2003; 46: 182–189.
10.1159/000071460
CASPubMedWeb of Science®Google Scholar
34 Chang ML, Chien RN, Yeh CT, Liaw YF. Virus and transaminase levels determine the emergence of drug resistance during long-term lamivudine therapy in chronic hepatitis B. J Hepatol 2005; 43: 72–77.
10.1016/j.jhep.2005.02.021
CASPubMedWeb of Science®Google Scholar
35 Zollner B, Petersen J, Schroter M, Laufs R, Schoder V, Feucht HH. 20-fold increase in risk of lamivudine resistance in hepatitis B virus subtype adw. Lancet 2001; 357: 934–935.
10.1016/S0140-6736(00)04219-7
CASPubMedWeb of Science®Google Scholar
36 Zollner B, Stoehr A, Plettenberg A et al. In vivo dynamics and pathogenicity of wild type and resistant Hepatitis B virus during long-term lamivudine monotherapy – a clinical note. J Clin Virol 2000; 17: 183–188.
10.1016/S1386-6532(00)00092-5
CASPubMedWeb of Science®Google Scholar
37 Gutfreund KS, Williams M, George R et al. Genotypic succession of mutations of the hepatitis B virus polymerase associated with lamivudine resistance. J Hepatol 2000; 33: 469–475.
10.1016/S0168-8278(00)80284-6
CASPubMedWeb of Science®Google Scholar
38 Honkoop P, Niesters HG, De Man RA, Osterhaus AD, Schalm SW. Lamivudine resistance in immunocompetent chronic hepatitis B. Incidence and patterns. J Hepatol 1997; 26: 1393–1395.
10.1016/S0168-8278(97)80476-X
CASPubMedWeb of Science®Google Scholar
39 Lai CL, Chien RN, Leung NW et al. A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med 1998; 339: 61–68.
10.1056/NEJM199807093390201
CASPubMedWeb of Science®Google Scholar
40 Lau DT, Khokhar MF, Doo E et al. Long-term therapy of chronic hepatitis B with lamivudine. Hepatology 2000; 32: 828–834.
10.1053/jhep.2000.17912
CASPubMedWeb of Science®Google Scholar
41 Liaw YF. Impact of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. Antivir Chem Chemother 2001; 12: 67–71.

CASPubMedGoogle Scholar
42 Locarnini S, McMillan J, Bartholomeusz A. The hepatitis B virus and common mutants. Semin Liver Dis 2003; 23: 5–20.
10.1055/s-2003-37587
CASPubMedWeb of Science®Google Scholar
43 Chen RY, Edwards R, Shaw T et al. Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro. Hepatology 2003; 37: 27–35.
10.1053/jhep.2003.50012
CASPubMedWeb of Science®Google Scholar
44 Hunt CM, McGill JM, Allen MI, Condreay LD. Clinical relevance of hepatitis B viral mutations. Hepatology 2000; 31: 1037–1044.
10.1053/he.2000.6709
CASPubMedWeb of Science®Google Scholar
45 Buckwold VE, Xu Z, Chen M, Yen TS, Ou JH. Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J Virol 1996; 70: 5845–5851.
10.1128/jvi.70.9.5845-5851.1996
CASPubMedWeb of Science®Google Scholar
46 Tacke F, Gehrke C, Luedde T, Heim A, Manns MP, Trautwein C. Basal core promoter and precore mutations in the hepatitis B virus genome enhance replication efficacy of Lamivudine-resistant mutants. J Virol 2004; 78: 8524–8535.
10.1128/JVI.78.16.8524-8535.2004
CASPubMedWeb of Science®Google Scholar
47 Akuta N, Suzuki F, Kobayashi M et al. Virological and biochemical relapse according to YMDD motif mutant type during long-term lamivudine monotherapy. J Med Virol 2003; 71: 504–510.
10.1002/jmv.10519
CASPubMedWeb of Science®Google Scholar

Citing Literature

Volume14, Issue11

November 2007

Pages 767-774

Differences of YMDD mutational patterns, precore/core promoter mutations, serum HBV DNA levels in lamivudine-resistant hepatitis B genotypes B and C

Abstract

References

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Differences of YMDD mutational patterns, precore/core promoter mutations, serum HBV DNA levels in lamivudine-resistant hepatitis B genotypes B and C

Abstract

References

Citing Literature

References

Related

Information